Diagnosis of schizophrenia has not changed over the last 100 years since Emil Kraepelin first defined the disease and is still based on evaluation of signs and symptoms in clinical interviews. If a patient does not acknowledge the occurrence of symptoms of psychosis, such as hallucinations and delusions, the disease can remain undiagnosed. In addition, some of the symptoms also occur in patients with mood and personality disorders and therefore misdiagnosis is a common occurrence. For example, Gonzalez-Pinto and co-workers found that approximately one-third of bipolar patients were diagnosed with schizophrenia (Bromet E. J. et al. (2005) Schizophr. Bull. 31(3):639-49). Another complication and reason for delay in diagnosis of schizophrenia is the insidious disease onset. Over the last two decades, the concept of prodromal schizophrenia, also referred to as ultra-high risk syndrome, has been a major focus of schizophrenia research. Research has shown that 20-30% of ultra-high risk individuals develop schizophrenia over a two to three year period (Fusar-Poli P. et al. (2012) Arch. Gen. Psychiatry 69(3):220-9). The prodromal syndrome is characterized on the basis of structured clinical interviews, which evaluate disturbances in perception, thought processing, language and attention (Fusar-Poli P. et al. (2014) Annu. Rev. Clin. Psychol.).
Early diagnosis of schizophrenia, ideally before or during the prodromal stages, would be beneficial for the outcome of patients. Long duration of untreated psychosis has been linked to poorer outcomes and there is evidence that early intervention or treatment can improve the outcome or even prevent the onset of schizophrenia (van der Gaag M. et al. (2013) Schizophr. Res. 149(1-3):56-62). The recent revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) has initiated discussion on the validity of the prodromal syndrome as a potential diagnostic category, which has now been listed in the appendix of DSM-5 as a “condition for further systematic study” (Tandon R. (2013) Schizophr. Res. 150(1):1-2). One critical concern is that approximately 70% of individuals who fulfill prodromal criteria do not develop schizophrenia and incorrect diagnosis would result in unwarranted treatment and stigma (Fusar-Poli P. et al. (2014) Annu. Rev. Clin. Psychol.).
Regulatory health authorities such as the Food and Drug Administration (FDA) have called for efforts to incorporate new methods such as biomarker applications to improve diagnosis and for delivery of more efficacious and safer drugs (Owens J. (2006) Nat. Rev. Drug Discov. 5(4):271). The FDA has defined three types of biomarkers: 1) exploratory biomarkers, 2) probable valid biomarkers and 3) known valid biomarkers (Goodsaid F. and Frueh F. W. (2007) Environ. Mol. Mutagen. 48(5):354-8). The third class is the most stringent as this requires replication of results at different sites, for cross-validation purposes.
A recently reported approach based on multiplexed immunoassay profiling, resulted in identification of a serum biomarker panel that could identify first-onset schizophrenia patients with an accuracy of 83% (Schwarz E. et al. (2012) Mol. Psychiatry. 17(5):494-502). However, this test was developed to differentiate schizophrenia patients from healthy controls, whereas psychiatrists place great clinical importance on development of blood tests that would help in the prediction of prodromal conversion and which could be used for differential diagnosis (e.g. differentiation between schizophrenia and affective psychosis).
Therefore, there is a need to develop an objective test, in particular a blood-based molecular biomarker test, for identification of schizophrenia prior to disease onset.